On Monday March 4 at the Conference
on Retroviruses and Opportunistic Infections (CROI) in Atlanta, details were
presented on a case of a potential “functional cure” of HIV infection in an
infant. The story has already broken widely in the media due to a CROI press
conference held on Sunday afternoon, during which the researcher describing the
case, Deborah Persaud, gave a preview of the data. The webcast of Persaud’s
talk is now available for viewing online (it is the seventh presentation in the session
entitled “Is There Hope for HIV Eradication?”).
The context of the case report is unusual because the mother
was not diagnosed with HIV infection until in labor, and there was no
opportunity to give her antiretroviral therapy (ART) to reduce the risk of
mother-to-child transmission. The infant was therefore considered at high risk
of acquiring infection, and HIV DNA and RNA tests were performed at 30 and 31
hours after birth, respectively. The HIV DNA test was positive, and the RNA
test showed a viral load of 19,812 copies. Although current U.S. guidelines
recommend initiating a prophylactic regimen of AZT and nevirapine pending the
results of virological testing, the treating pediatrician, Hannah Gay, chose to
initiate combination ART including AZT, 3TC, and nevirapine (the latter at the
therapeutic rather than prophylactic dose). Nevirapine was switched in favor of
Kaletra after seven days. Subsequent sequential viral-load testing showed the
typical decline in response to treatment, with measurements of 2,617 copies, 516
copies, 265 copies and then less than 48 copies (beneath the limit of
detection).
ART was maintained for around 18 months until the mother and infant were lost
to follow-up. When the infant was returned to care around five months later,
Gay learned that treatment had been stopped. The reasons for the disengagement
from care and cessation of treatment have not been made clear, with Gay stating in one article only that the mother was battling “some life changes.”
Testing of the infant after the return to care revealed a
highly unusual outcome: viral load remained undetectable despite the five-month
period off ART (there have been many studies of pediatric ART interruptions, all demonstrating that viral-load
rebound occurs rapidly, typically to very high levels, almost without
exception). This prompted Gay to consult with external experts in pediatric HIV
infection Deborah Persaud at Johns Hopkins University and Katherine Luzuriaga at Massachussetts General Hospital. The
results of further investigations led to the findings presented by Persaud at
CROI: several independent laboratories with expertise in searching for trace
amounts of HIV evaluated samples from the infant but could only rarely detect
extremely low levels of viral genetic material (there was no detectable
replication-competent HIV).
These results echo those from follow-up studies of
the single adult considered cured of HIV infection, Timothy Brown. Methods
employed included digital droplet PCR, single-copy assays for HIV RNA, and a test for viral outgrowth from 22 million resting CD4 T cells. Immune responses to HIV, including antibody and CD4
and CD8 T-cell responses, were not detectable. Genetic studies showed that neither
mother nor infant possessed the CCR5-Delta32 mutation or any HLA genes known to
be associated with control of HIV replication. The totality of the findings has
led the researchers to conclude that the infant represents a case of a
functional cure of HIV infection (essentially an infant equivalent of Timothy
Brown); the virus may not have been completely cleared, but at the current
time—after over 10 months off ART—no viral activity is detectable.
Not too surprisingly, the media interest in the story has
been intense. Several stories, including a piece in the New York Times, have
included quotes from scientists suggesting the possibility that the infant was
not infected in the first place. This scenario is difficult to reconcile with
the stepwise decline in HIV RNA levels after ART initiation (this would have to
involve not only four sequential false positive RNA results, but false positive
results that also coincidentally mirrored the expected viral-load decline in
response to ART—a possibility that seems vanishingly unlikely). Another
skeptical viewpoint cited by some articles is that HIV might have been cleared
even in the absence of ART. This suggestion is based on occasional reports in the scientific literature of apparent
transient HIV infection in exposed infants; however, a study published in 1998 that analyzed many
of these cases in detail showed that most were explained by PCR testing
contamination or sample mislabeling. Even the few reports that could not be
fully explained by these problems were considered to be lacking the evidence
necessary to formally prove that transient infection had occurred.
Some other aspects of the case deserve comment: although the
baseline viral load of 19,812 copies might seem relatively low in the context
of adult values, it should be noted that data on early viral loads among
infected infants indicate this level is not atypical. A study published in 1998 reported that “all 18
infants defined as in utero infected by DNA PCR or coculture (or both) were
also positive with a wide range of plasma HIV-1 RNA values within 48 h of birth
and a median level of 26,940 HIV-1 RNA copies/mL (25th and 75th percentiles,
1,556 and 468,390).”
In terms of other cases of pediatric ART interruptions in
which viral-load rebound did not occur, a search of the literature did not turn
up many examples. In 2006, researchers from Massachusetts General Hospital published a case report regarding a perinatally
infected child who stopped ART as a teenager and maintained undetectable viral-load levels for five years of follow-up; the individual was heterozygous for
the CCR5-Delta32 mutation and, unlike the infant described by Persaud,
displayed strong HIV-specific T-cell responses. A 2008 survey of outcomes among children and adolescents undergoing
unstructured ART interruptions notes the following: “In only
1 patient (6% [1 of 17]) did HIV-1 RNA remain undetectable after 12 months off
therapy.” However, no additional information is provided, and the cut-off for
the viral-load assay used was <400 copies.
Based on the data presented, the Persaud case report appears unique, and the evidence that HIV infection occurred and has subsequently
been controlled or even cleared after short-term ART is more compelling than
some of the skeptical comments in the press have suggested. However, there is a
lack of stored samples that might be able to bolster the evidence by confirming
the genetic relationships between the separate virus samples from the infant and
the linkage to the virus in the mother. It also remains possible that viral
load could rebound at some point in the future.
The implications for pediatric HIV care and cure research are
now the subject of ongoing discussions:
- Most basically, the case raises questions about
the accessibility and quality of the health care system in Mississippi and the
U.S. generally (as eloquently described in a posting by Jim Merrell of the Prevention Justice Alliance). - Deborah Persaud has cited the possibility of
studying triple-combination ART instead of the normally recommended dual-prophylactic regimen of AZT and nevirapine in infants with HIV-positive mothers
who have not received prophylaxis, in order to assess whether similar outcomes
can be obtained (the British HIV Association guidelines
already recommend triple-drug therapy as postexposure prophlylaxis for infants
whose mothers have detectable viral loads at delivery). - For other perinatally infected children treated
very early with ART, it has been suggested that there is now reason to
carefully study whether control of HIV might be maintained after ART interruption
(the reason that many ART interruption studies have already been conducted in
the pediatric population is the recognition that they face the greatest burden
of lifelong treatment). A related proposal is that perinatally infected
children on ART should be candidates for studies of approaches that might
increase the possibility of HIV control after ART withdrawal (such as
therapeutic vaccines). A poster presentation at CROI by Katherine Luzuriaga describes five early-treated
children in whom no replication-competent HIV can be detected, and makes the
point that these individuals are “prime candidates for interventions to achieve
functional cure or eradication.” - More broadly for the cure research field, the
case suggests that early ART may have prevented the establishment of a long-lived
latent reservoir of HIV-infected memory CD4 T cells. This suggestion fits with
current efforts to deplete the latent HIV reservoir as a means to a cure. - The question whether very early ART could
lead to a similar outcome in adults might potentially be addressed by another ongoing study presented at CROI by Jintanat Ananworanich from Thailand,
which involves a sizable population of individuals initiating ART at the very
earliest stage of acute HIV infection (Feibig I). Ananworanich reported that
the majority of individuals treated at this stage showed undetectable levels of
integrated HIV DNA in both the blood and colon after 24 weeks of ART; future plans
include analytical treatment interruptions to assess whether HIV viral load
returns.
Update 3/14/2013: On Monday March 11th in the Wall Street Journal, Dr. Mark J. Siedner from Massachussetts General Hospital and Harvard Medical School published an opinion piece arguing that the case represents an example of successful infant post-exposure prophlaxis (PEP) against HIV infection, rather than a cure of HIV infection that had occurred in utero as Persaud and colleagues have suggested. There is a published case report of an adult recipient of an HIV-infected blood transfusion who showed a single viral load value of 3 copies/mL (the lower limit of detection of the assay) but proved to be uninfected after receipt of PEP. However, there are also published studies that include assessments of viral load values in infants receiving PEP to prevent mother-to-child transmission and none appear to offer examples consistent with the idea that viral load values are detectable in this situation e.g. see this large French study from 2012, and a US analysis from 2003; the latter reports two examples of low values in infants receiving AZT prophlyaxis, but they are considered false positives because DNA PCR tests taken the same day were negative (unlike the case reported at CROI).
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